In vivo, necrotic cell death almost inevitably provokes an inflammatory response (Majno et al., “Cellular death and necrosis: chemical, physical and morphologic changes in rat liver,” Virchows Arch. Pathol. Anat. Physiol. Klin. Med., 333:421-465, 1960). Within minutes, there is an influx of neutrophils and at later times monocytes into injured tissues. This response is elicited by most types of injured cells and is so stereotypical that it is used to help identify cell death in vivo and even estimate the time at which it occurred, e.g., after an ischemic insult such as a myocardial infarction (Antman, Acute myocardial infarction. In Heart Disease: A Textbook of Cardiovascular Medicine, 6th ed. B. E., Z. D. P., and L. P., editors. Philadelphia, Pa.: WB Saunders. 1114-1231, 2001). This sterile inflammatory response to injured cells is medically important. Acutely, it can cause pain, dysfunction and further tissue damage that may actually do more harm than good, in at least some settings. Chronically, the sterile inflammation provoked by ongoing tissue damage is thought to contribute to the pathogenesis of many diseases, including ischemia-induced injuries (Fisher and Meiselmann, “Polymorphonuclear leukocytes in ischemic vascular disease,” Thromb. Res., 74 Suppl. 1:S21-34, 1994), rheumatoid arthritis (Wipke and Allen, “Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis,” J. Immunol. 167:1601-1608, 2001; Chen et al., “Neutrophil-derived leukotriene B4 is required for inflammatory arthritis,” J. Exp. Med. 203:837-842, 2006; Kim et al., “A unique requirement for the leukotriene B4 receptor BLT1 for neutrophil recruitment in inflammatory arthritis,” J. Exp. Med., 203:829-835, 2006), acute lung injury (Abraham, “Neutrophils and acute lung injury,” Crit. Care Med. 31:S195-199, 2003), drug-induced liver injury (Liu et al., “Neutrophil depletion protects against murine acetaminophen hepatotoxicity,” Hepatology 43:1220-1230, 2006), inflammatory bowel diseases (Zingarelli et al., “Blockade of Poly(ADP-ribose) synthetase inhibits neutrophil recruitment, oxidant generation, and mucosal injury in murine colitis,” Gastroenterology, 116:335-345, 1999). It is therefore important to elucidate the mechanisms underlying the sterile inflammatory response to injured cells. Ultimately, these mechanisms might be important targets of pharmacological intervention.
The inflammatory response to dying tissues is thought to serve several functions. Cell death may help to alert the immune system to potential danger such as an infection. The ensuing inflammatory response rapidly mobilizes leukocytes that attempt to contain and/or eliminate an infection, if present. Even if an infection isn't present, the recruited leukocytes play an important role in removing the dead cells and stimulating tissue repair mechanisms (Serhan and Savill, “Resolution of inflammation: the beginning programs the end,” Nat. Immunol., 6:1191-1197, 2005; Fadok et al., “Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF,” J. Clin. Invest., 101:890-898, 1998; Huynh et al., “Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-betal secretion and the resolution of inflammation,” J. Clin. Invest., 109:41-50, 2002). While these aspects of the inflammatory response are beneficial, the recruited leukocytes can also damage healthy cells. In the absence of infection, this “sterile inflammation” may cause dysfunction and disease (Sadasivan et al., “Neutrophil mediated microvascular injury in acute, experimental compartment syndrome,” Clin. Orthop. Relat. Res., 206-215, 1997; Bless et al., “Protective effects of an aptamer inhibitor of neutrophil elastase in lung inflammatory injury,” Curr. Biol. 7:877-880, 1997; Sawa et al., “Leukocyte depletion attenuates reperfusion injury in patients with left ventricular hypertrophy,” Circulation, 93:1640-1646, 1996; Sekido et al., “Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8,” Nature, 365:654-657, 1993; Jaeschke, “Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions,” Am. J. Physiol. Gastrointest. Liver Physiol., 290:G1083-1088, 2006). It is therefore important to understand the basis of the sterile inflammatory response to tissue injury.